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La acetilmetilisina marca la cromatina en los sitios de inicio de la transcripción activa
William J Lu-Culligan1,2, Leah J Connor1,2, Yixuan Xie3
1Department of Molecular Biophysics & Biochemistry, Yale University, New Haven, CT, USA.
Nature
|September 21, 2023
Resumen
Los investigadores descubrieron una nueva modificación de la proteína, Nε-acetil-Nε-metilisina (Kacme), donde los residuos de lisina son tanto metilados como acetilados. Esta doble modificación, encontrada en la histona H4, está relacionada con la cromatina activa y la expresión génica.
Área de la Ciencia:
- Biología molecular
- La epigenética
- Modificaciones posteriores a la traducción
Sus antecedentes:
- Los residuos de lisina en las proteínas sufren modificaciones post-traduccionales (PTM) como la acetilación y la metilación, cruciales para regular la cromatina y la expresión génica.
- Estos PTM son objetivos clave para las intervenciones terapéuticas en diversas enfermedades humanas.
- Se creía ampliamente que la metilación de lisina y la acetilación se excluían mutuamente en el mismo residuo.
Objetivo del estudio:
- Identificar y caracterizar una nueva modificación de residuos de lisina celular que involucra la acetilación y la metilación simultáneas.
- Investigar la aparición, la regulación y las implicaciones funcionales de esta doble modificación en la biología de la cromatina.
Principales métodos:
- Identificación de la Nε-acetil-Nε-metilisina (Kacme) en las proteínas celulares, específicamente en la histona H4 (H4Kacme).
- Análisis de la presencia de H4Kacme en especies y tejidos de mamíferos.
- Ensayos para determinar la asociación de H4Kacme con las marcas de cromatina activa y la actividad transcripcional.
- Estudios enzimáticos in vitro sobre la formación de H4Kacme y su estabilidad frente a la desacetilación.
- Análisis estructural mediante cristalografía de rayos X de la proteína BRD2 unida a un péptido H4Kacme.
Principales resultados:
- Descubrimiento de Nε-acetil-Nε-metilisina (Kacme), un residuo metilado y acetilado simultáneamente, en la histona H4 (H4Kacme) en diversas especies y tejidos.
- H4Kacme está correlacionado con las marcas de cromatina activa, mejora la iniciación transcripcional y responde a las señales biológicas.
- H4Kacme puede formarse enzimáticamente y exhibe resistencia a ciertas desacetilasas; su estructura revela la unión por proteínas reconocedoras de acetillisina como BRD2.
Conclusiones:
- Kacme representa una nueva modificación post-traduccional con el potencial de transmitir información reguladora distinta de la metilación o la acetilación aisladas.
- Los hallazgos establecen a Kacme como un PTM significativo en la biología de la cromatina, con implicaciones fundamentales para la comprensión de la regulación génica.
- El descubrimiento abre nuevas vías para explorar la compleja interacción de las PTM de lisina en los procesos celulares y las enfermedades.
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